C. La Casa

Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions.

This study was designed to determine the ulcer-protecting effects of rutin, a natural flavone, against gastric lesions induced by 50% ethanol, the experimental model related to lesion pathogenesis with production of reactive species. The possible involvement of sulphydryl compounds (SH), neutrophil infiltration, and the capacity of this flavone to restrain the oxidative process produced in the gastric tissue were also investigated. The levels of thiobarbituric acid (TBA, as index of lipid peroxidation), the myeloperoxidase activity (MPO, as a marker of neutrophil infiltration), the content of mucosal sulphydryls (SH) groups and the activity of glutathione peroxidase (GSH-Px, an important antioxidant enzyme) were determined. Pretreatment with the highest dose of rutin (200 mg/kg), 120 min before 50% ethanol, resulted in the most effective necrosis prevention. TBA reactive substances in the gastric mucosa, were increased by ethanol injury, and this increase was inhibited by the administration of 200 mg/kg of rutin. However, the flavonoid was not able to modify the ethanol-induced neutrophil infiltrate expressed as myeloperoxidase activity. Exposure of the gastric mucosa to 50% ethanol induced a significant diminution in gastric non-protein SH content; this parameter also was not modified by the treatment with rutin. GSH-Px activity decreased in the gastric mucosa after ethanol-treatment. In contrast, rutin at all tested doses induced a significant increase in this enzymatic activity, higher than in control group. These results suggest that the gastroprotective effect of rutin in this experimental model appears through an anti-lipoperoxidant effect, and also by enhancement of the anti-oxidant enzymatic (GSH-Px) activity.

Anti-oxidant mechanisms involved in gastroprotective effects of quercetin.

Abstract The anti-ulcerogenic and anti-oxidant effects of various flavonoids have been frequently reported. We investigated the cytoprotective properties of quercetin, a natural flavone, in gastric mucosal injury induced by 50% ethanol, since in this experimental model the pathogenesis of the lesions has been related with production of reactive oxygen species. The involvement of neutrophil infiltration and the capacity of this flavonoid to restrain the oxidative process produced in the gastric tissue after ethanol administration were also investigated. Oral pretreatment with the highest dose of quercetin (200 mg/kg), 120 min before absolute ethanol was the most effective anti-ulcer treatment. Thiobarbituric acid reactive substances in the gastric mucosa, an index of lipid peroxidation, were increased by ethanol injury, but the increase was inhibited by the administration of 200 mg/kg of quercetin. This dose also induced a significant enhancement in the levels of mucosal non-protein SH compounds (important anti-oxidant agents) and in glutathione peroxidase activity. Exposure of the gastric mucosa to 50% ethanol induced a significant increase in myeloperoxidase activity, an index of neutrophil infiltration. Flowever, quercetin was not able to modify the increase in enzymatic activity generated by the necrotizing agent. The activity of superoxide dismutase enzyme involved in several antioxidant processes was also not significantly modified after quercetin treatment. These results suggest that the anti-ulcer activity of quercetin in this experimental model could be partly explained by the inhibition of lipid peroxidation, through decrease of reactive oxygen metabolites. However, the inhibition of neutrophil infiltration or the increase of superoxide dismutase activity does not appear to be involved in gastroprotective effect of this flavonoid.

Antiulcerogenicity of the flavonoid fraction from Bidens aurea: Comparison with ranitidine and omeprazole

Effects of the flavonoid fraction of Bidens aurea (Aiton) Sherff on gastric ulceration induced by restraint and cold were studied in rats. Mucosal damage was evaluated histomorphometrically and the results were compared with those of omeprazole and ranitidine. The effects of these agents on the quantity and quality of the gastric mucus were also determined histologically and biochemically. Oral treatment with the ether fraction of the flavonoid extract gave the highest level of gastric protection. Mucus content was increased and accompanied by a proportional increase in proteins and hexosamines. There was also a marked increase of the periodic acid-Shiff (PAS) area (neutral glycoprotein) and the alcian blue (AB) area (sulphated glycoprotein). The groups which received ranitidine and omeprazole did not overcome the inhibition of the mucus secretion induced in this experimental model.

Effects of oxicam inhibitors of cyclooxygenase on oxidative stress generation in rat gastric mucosa. A comparative study.

The aim of this study was to compare the effects of two nonsteroidal anti-inflammatory drugs (NSAID), members of the same family with a different cyclooxygenase (COX) inhibition selectivity, meloxicam, preferent COX-2 inhibitor, and piroxicam, preferent COX-1 inhibitor, on oxygen radical generation in rat gastric mucosa. Therefore, the activity of oxidative stress-related enzymes such as xanthine oxidase (XO), superoxide dismutase (SOD) and glutathione (GSH) homeostasis were studied in rats. Gastric prostaglandins (PG) were also assessed as a measure of COX-1 inhibition. Both oxicams produced a similar extent of the gastric mucosal damage and a significant decrease in PGE 2 synthesis, however only piroxicam induced an increase of both myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)- f content in the gastric mucosa, indicating that neutrophil-derived free radicals were involved in gastric injury. Furthermore, both compounds reduced SOD activity and increased XO activity in gastric mucosa. Our results also revealed modifications in GSH metabolism: although glutathione peroxidase (GSH-px) activity was unaffected by meloxicam or piroxicam administration, both glutathione reductase (GSSG-rd) activity and total GSH content were significantly decreased after dosing. These results suggest that under our experimental conditions, meloxicam, preferential COX-2 inhibitor causes rates of gastric lesion in rats comparable to those seen with the traditional NSAID piroxicam, preferential COX-1 inhibitor. In addition to suppression of systemic COX activity, oxygen radicals, probably derived via the XO, and neutrophils play an important role in the production of damage induced by both oxicams. Moreover, the decrease in SOD activity and changes in glutathione homeostasis in gastric mucosa may also contribute to pathogenesis of meloxicam- or piroxicam-induced gastropathy.

Effects of meloxicam on oxygen radical generation in rat gastric mucosa.

Abstract.Aim and Design: In addition to a deficiency of endogenous prostaglandins due to inhibition of cyclo-oxygenase and a host of prostaglandin-mediated effects on mucosal protection, it has recently been proposed that neutrophil- and oxygen radical - dependent microvascular injuries may be important prime events that lead to mucosal injury induced by non-steroidal anti-inflammatory drugs. Therefore, we evaluated the role of oxygen free radicals in the pathogenesis of acute gastric ulceration induced by meloxicam, a preferential COX-2 inhibitor.¶Material: Studies were performed in Wistar rats.¶Treatment: Meloxicam was given by oral administration (3.75-30 mg/kg body weight).¶Methods: Determinations were made of gastric mucosal injury, xanthine-oxidase, myeloperoxidase and superoxide dismutase activities, as well as the effect of meloxicam on gastric prostaglandin synthesis (PGE2 levels) and glutathione homeostasis.¶Results: Oral administration of meloxicam dose-dependently (3.75-30 mg/kg) caused acute gastric haemorrhage erosions. The total area of gastric lesions increased with time until 24 hours after dosing. Xanthine-oxidase activity increased significantly after administration of the drug. Myeloperoxidase activity, as an index of neutrophil infiltration, as well as glutathione peroxidase, an important enzyme that scavenges lipid peroxides, were unaffected by meloxicam administration. In addition, superoxide dismutase activity, PGE2 and glutathione levels were significantly reduced.¶Conclusion: These results support the hypothesis that in addition to suppresion of prostaglandin synthesis, oxygen free radicals, probably derived via the action of xanthine oxidase, the decrease in superoxide dismutase activity, and the depletion of mucosal glutathione contribute to the pathogenesis of meloxicam-induced ulceration.

Cytoprotective activity of cisapride on experimental gastric mucosal lesions induced by ethanol. Role of endogenous prostaglandins

The antiulcer effects and protective mechanisms of cisapride, a prokinetic benzamide agonist of 5-HT3 and antagonist of 5-HT4 receptors, were investigated in gastric mucosal injury induced by pretreatment with 50% v/v ethanol in rats. The duration of the protective effect was also studied and the results were compared with those of 5-HT. 240 min after administration of cisapride (10, 25 and 50 mg/kg) the total area of gastric lesions decreased significantly, in macroscopical and histological evaluations, and the mucus, hexosamine, and sulphated glycoprotein content were significantly increased. Indomethacin partially reversed cisapride protection suggesting that the beneficial antiulcer effects of this drug could be mediated in part by prostaglandins. This study confirms that this benzamide, in this experimental model, enhances gastric PGE2 production. We also investigated the time course of action of 5-HT, 30-240 min before ethanol administration, and our study not only demonstrates the ulcerogenic action of the amine (30 min of pretreatment) but also its protective nature, shown macroscopic and microscopically, after 240 min of its administration, without any effect on PGs production. These findings suggest a new gastroprotective feature of cisapride partly explained through a prostaglandin-dependent mechanism and possibly independent of its 5-HT activity.

Cinitapride protects against ethanol-induced gastric mucosal injury in rats: role of 5-hydroxytryptamine, prostaglandins and sulfhydryl compounds.

This study was designed to determine the gastroprotective properties of cinitapride (CNT), a novel prokinetic benzamide derivative agonist of 5-HT4 and 5-HT1 receptors and 5-HT2 antagonist, on mucosal injury produced by 50% (v/v) ethanol. Results were compared with those for 5-hydroxytryptamine (5-HT: 10 mg kg-1). The possible involvements of gastric mucus secretion, endogenous prostaglandins (PGs) and sulfhydryl compounds (SH) in the protection mediated by CNT were also examined. Intraperitoneal administration of CNT (0.50 and 1 mg kg-1), 30 min before ethanol, significantly prevented gastric ulceration and increased the hexosamine content of gastric mucus. CNT (1 mg kg-1) also produced a significant increase in gastric mucosal levels of PGE2, but did not induce any significant changes in SH values. On the contrary, pretreatment with 5-HT worsened ethanol-induced erosions, however, did not affect gastric mucus secretion, glycoprotein content or PGE2 levels, although the non-protein SH fraction was significantly decreased. The present results demonstrate that the gastroprotective effects of CNT could be partly explained by a complex PG dependent mechanism. We suggest that 5-HT dependent mechanisms through 5-HT2 receptor blockade and 5-HT1 receptor activation could be also involved.

Effects of cinitapride on gastric ulceration and secretion in rats

Abstract.Objective and Design: The aim of the present study was to examine the effects of cinitapride, a novel prokinetic benzamide-stimulating gastrointestinal motility agent, on gastric secretion and ulceration in rats and elucidate some possible vascular and anti-oxidant mechanisms of such protection.¶Material: Male Wistar rats.¶Treatment: Cinitapride (CNT, Lab. Almirall, S.A.) (0.25, 0.5, and 1 mg/kg) and 5-hydroxytryptamine (5-HT, Sigma Chemical Co., St. Louis, MO, USA) (10 mg/kg), administered intraperitoneally (i.p.).¶Methods: Gastric ulceration was induced by instillation of 1 mL/100 g animal of 50% (v/v) ethanol in distilled water and by pylorus-ligated rat model. Gastric microvascular changes, and the activity of myeloperoxidase (as a marker of neutrophil infiltration) and glutathione peroxidase (an important enzyme in scavenging of lipid peroxides) were determined. The results were compared with those of 5-HT. The data were evaluated using Student’s t-test for paired data and the non-parametric Mann-Whitney U-test.¶Results: In 4 h pyloric-ligated animals, i.p. CNT did not significantly reduce the incidence of gastric mucosal damage, and no significant differences were found in the values of total volume and acidity. However, CNT caused a marked and dose-dependent reduction of haemorrhagic lesions induced by 50% v/v ethanol. These protective effects were specifically related to a reduction of neutrophil infiltration. CNT at the dose of 1 mg/kg raised the decreased glutathione peroxidase activity to the control level. In contrast, pretreatment with 5-HT worsened the ethanol-induced erosions, but did not significantly induce any gastric microvascular changes. However, the myeloperoxidase activity rose markedly and the glutathione peroxidase levels decreased significantly in the mucosa injured by 50% v/v ethanol.¶Conclusions: This study demonstrates a new gastroprotective feature of CNT that could be partly explained not only through reduction of neutrophil toxicity but also by an increased synthesis of free-radical scavenging enzymes such as glutathione peroxidase. Furthermore, it is likely that serotonergic-dependent mechanisms are also involved via 5-HT2-receptor blockade and 5-HT1 receptor activation.

Ulcer-protecting effects of a flavonoid fraction from Bidens aurea. Role of endogenous prostaglandins and microvascular permeability.

This study was designed to determine the ulcer-protecting effects of a flavonoid fraction obtained from the flowers of Bidens aurea (Aiton) Sherff against gastric lesions induced by absolute ethanol. The possible involvement of gastric mucus secretion, endogenous prostaglandins (PGs) and mucosal microvascular permeability (MVP) in the protection mediated by the flowers of B. aurea were also determined. Flavonoid fraction pretreatment (250 mg/kg) 120 min before absolute ethanol was most effective in necrosis prevention. There was also a marked increase (p < 0.001) in hexosamine content. Intraperitoneal administration of indomethacin (IND) (10 mg/kg) partially inhibited gastric protection and the values of PGE(2) were significantly (p < 0.001 and p < 0.05) augmented. In addition, administration of 250 mg/kg of the extract reduced the elevated MVP induced by alcohol in rat gastric mucosa. These results demonstrate that the gastroprotective effects of B. aurea flowers could be partly explained through a complex prostaglandin-dependent mechanism involving stimulation of mucus glycoprotein content and reduction of MVP values.

Antiulcer and Antidiarrhoeic Effect of Baccharis teindalensis

Baccharis teindalensis is a herbal plant which is widely used in folk medicine in Ecuador as an antiinflammatory, analgesic and antimicrobial remedy. This study deals with the isolation and investigation of the main active principles of its ethanol extract, especially polyphenolic compounds belonging to the flavonoid family. Moreover, we have evaluated the antidiarrhoeic and antiulcer activities of this extract in different mouse models. The ethanol extract of B. teindalensis showed antidiarrhoeic activity against the castor oil induced diarrhoea, at all doses tested. The dose of 100mg/kg significantly retarded the appearance of first diarrhoeic faeces (p < 0.01) and decreased the percentage of wet faeces excreted in the following four hours after administration of the cathartic agent. Both assayed doses (50 and 100 mg/kg) decreased the total weight of excreted diarrhoeic faeces (p < 0.01). On the other hand, oral pretreatment with a 100 mg/kg dose considerably diminished absolute ethanol-induced gastric ulcers (p < 0.001), whereas the lowest dose of B. teindalensis did not improve the mucosal macroscopic appearance. Furthermore, the ethanol extract induced a significant increase in myeloperoxidase activity as an index of the neutrophilic infiltration (p < 0.05 vs control) and the higher dose of this extract (100 mg/kg) inhibited it in a remarkable way (p < 0.001). These results confirm the gastrointestinal protection afforded by B.teindalensis and suggest that the antiulcer effect could be partially due to its antiinflammatory properties.